Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level

Carlos Romá-Mateo, Daniel Moreno, Santiago Vernia, Teresa Rubio, Travis M. Bridges, Matthew S. Gentry, Pascual Sanz

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Background: Malin is an E3-ubiquitin ligase that is mutated in Lafora disease, a fatal form of progressive myoclonus epilepsy. In order to perform its function, malin forms a functional complex with laforin, a glucan phosphatase that facilitates targeting of malin to its corresponding substrates. While laforin phylogeny has been studied, there are no data on the evolutionary lineage of malin. Results: After an extensive search for malin orthologs, we found that malin is present in all vertebrate species and a cephalochordate, in contrast with the broader species distribution previously reported for laforin. These data suggest that in addition to forming a functional complex, laforin and perhaps malin may also have independent functions. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32, which belongs to the tripartite-motif containing family of proteins. We present experimental evidence that both malin and TRIM32 share some substrates for ubiquitination, although they produce ubiquitin chains with different topologies. However, TRIM32-specific substrates were not reciprocally ubiquitinated by the laforin-malin complex. Conclusions: We found that malin and laforin are not conserved in the same genomes. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32. The latter result suggests a common origin for malin and TRIM32 and provides insights into possible functional relationships between both proteins.

Original languageEnglish
Article number225
JournalBMC Evolutionary Biology
Volume11
Issue number1
DOIs
StatePublished - 2011

Bibliographical note

Funding Information:
We want to thank Dr. Santiago Rodriguez de Cordoba, Dr. Christine Blattner, Dr. Derek Blake and Dr. Manuel Rodriguez, for providing us the described plasmids and Dr. Ignacio Marin (IBV-CSIC, Valencia, Spain) for helpful discussions. This work was supported by a grant from the Spanish Ministry of Education and Science (SAF2008-01907) to PS; and by National Institutes of Health grants 5R00NS061803, 5P20RR0202171, 1R01NS070899 and University of Kentucky College of Medicine startup funds to M.S.G.

Keywords

  • AMPK
  • E3 ubiquitin ligase
  • Lafora disease
  • TRIM32
  • malin
  • phylogeny

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics

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